LDE225 (Sonidegib, Erismodegib) is a Smoothenced (SMO) target inhibitor developed by Novartis, and the drug is in multiple clinical trials for various diseases, including myelofibrosis, leukemia and solid tumors, such as basal cell carcinoma, angiocarcinoma, pancreatic cancer, breast cancer and non-small cell lung cancer. The chemical name of LDE225 is N-[6-(cis-2,6-dimethylmorpholine-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)[1,1′-biphenyl]-3-carboxamide, and the structure is shown as formula (I).

Different crystalline forms of the same compound are significantly different in appearance, solubility, melting point, dissolution rate, bioavailability and so on, thus affect stability, bioavailability and efficiency of drugs. Therefore, it is of great significance to develop new crystalline forms that are more suitable for drug development.
As is known to the skilled in the art, the presence of new solid polymorphic forms of a known chemical substance is unpredictable. The existence of the polymorphic compound or the number of the polymorphic forms is also unpredictable. In addition, it is also unpredictable under what conditions to obtain a specific form, and how are the characteristics of the polymorphic form. Since the properties of each polymorph of the compound (e.g., solubility, stability) cause the difference of use and storage, it is necessary to study all solid forms, including all polymorphic forms to provide drugs with improved storage stability or predictable solubility.
At present, CN10241249A disclosed crystalline Form A and Form B of free base of compound of formula (I), and CN102159570B disclosed crystalline forms of diphosphonate, monohydrochloride and monosulfate of compound of formula (I). Diphosphonate can increase the dissolution rate of free base and has relatively high in-vivo exposure, thus it is a preferred choice for drug development. However, CN102159570B disclosed that the XRPD of the crystalline form of diphosphonate is slightly changed, after it has been placed at 50° C./75% RH (relative humidity) for 2 weeks. The XRPD of the crystalline form of diphosphonate is changed after it has been placed at 80° C./75% RH for two weeks. Therefore, there is risk that the more preferred diphosphonate in prior art will have crystal transformation in transportation and storage.
The inventors of the present disclosure have surprisingly found two crystalline forms of compound of formula (I) monophosphate, and the diphosphonate disclosed in CN102159570B is not stable in solvents containing water or a biological medium, the diphosphonate would disproportionate and generate phosphoric acid in solvents containing water, which has a certain effect on the pH of in-vivo environment. Therefore, there is a need to find new crystalline forms which are stable in solvents containing water or biological media. The present disclosure shows that the stability of the monophosphate is better than that of diphosphonate, and the crystalline form A and crystalline form B of the monophosphate have homogeneous particle size and the dispersion is good. The monophosphate provided by the present disclosure has smaller molecular weight than that of the diphosphonate, and thus has higher content of active ingredients, so it can reduce dose and save cost, and is more suitable for drug development.
The crystalline forms of monophosphate in present disclosure have good stability and low hygroscopicity, good for storing, can avoid crystal transformation in the development and production of the drug. In addition, the monophosphate has similar solubility with that of diphosphonate, and has strong developing and economic value.